Geospatial Immune Heterogeneity Reflects the Diverse Tumor-Immune Interactions in Intrahepatic Cholangiocarcinoma
Geospatial Immune Heterogeneity Reflects the Diverse Tumor-Immune Interactions in Intrahepatic Cholangiocarcinoma
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DOI：
10.1158/2159-8290.cd-21-1640
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发表时间：
2022-10-01
期刊：
影响因子：
28.2
通讯作者：
Gao, Qiang
中科院分区：
文献类型：
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作者：
Lin, Youpei;Peng, Lihua;Gao, Qiang
肝内胆管细胞癌（iCCA）具有广泛的瘤内异质性和极高的死亡率。在这里，我们对45名iCCA患者的207个肿瘤区域进行了全外显子组测序、RNA测序、T细胞受体（TCR）测序和多重免疫荧光。半数以上的iCCA表现出瘤内免疫浸润的异质性，iCCA可分为稀疏、异质和高度浸润亚组，具有不同的免疫基因组学特征。稀疏浸润的肿瘤表现出克隆性新抗原的主动拷贝数丢失，异质性免疫浸润在跨肿瘤亚区的亚克隆进化中起重要作用。高度浸润的肿瘤的特征在于广泛的免疫激活和跨肿瘤亚区的相似TCR库，但与T细胞耗竭和普遍的抗原呈递缺陷相抵消。值得注意的是，FGFR 2突变和融合与低突变负荷和减少的免疫浸润相关。我们的工作描绘了动态的肿瘤-免疫相互作用，并开发了一个强大的分类系统，将iCCA患者分为具有不同疾病的高和低免疫逃避组。本研究阐明了空间免疫异质性对iCCA肿瘤演变的影响，并揭示了不同免疫微阵列中形成的不同免疫逃避机制，其可用于开发个性化的免疫治疗策略。
Intrahepatic cholangiocarcinoma (iCCA) exhibits extensive intratumoral hetero-geneity and an extremely high mortality rate. Here, we performed whole-exome sequencing, RNA sequencing, T-cell receptor (TCR) sequencing, and multiplexed immunofluorescence on 207 tumor regions from 45 patients with iCCA. Over half of iCCA displayed intratumoral het-erogeneity of immune infiltration, and iCCA were classified into sparsely, heterogeneously, and highly infiltrated subgroups with distinct immunogenomic characteristics. Sparsely infiltrated tumors dis-played active copy-number loss of clonal neoantigens, and heterogeneous immune infiltration played an important role in the subclonal evolution across tumor subregions. Highly infiltrated tumors were characterized by extensive immune activation and a similar TCR repertoire across tumor subregions, but counteracted with T-cell exhaustion and pervasive antigen presentation defects. Notably, FGFR2 mutations and fusions correlated with low mutation burden and reduced immune infiltration. Our work delineated the dynamic tumor-immune interactions and developed a robust classification system to divide patients with iCCA into high and low immune evasion groups with different prognoses.SIGNIFICANCE: This study elucidates the impact of spatial immune heterogeneity upon tumor evolution of iCCA and reveals distinct immune evasion mechanisms developed in different immune microenviron-ments, which can be exploited for the development of personalized immunotherapy strategies.